1. Acute MDMA administration modulates posterior cingulate cortex activity and functional connections with striatal-frontal circuits during evaluation of risk: MDMA use is associated with risk taking behavior, notably high-risk sexual behavior. We examined risky decision-making following acute MDMA administration. MDMA users performed the Rogers gambling task during fMRI after receiving placebo, low (1.0 mg/kg), or high (1.6 mg/kg) dose MDMA in a double-blind, within-subjects design. Acute MDMA administration dose-dependently modulated the activity of several brain regions, including middle frontal and superior parietal regions, and the posterior cingulate cortex (PCC), which is known to regulate risky decision-making. Further, MDMA dose-dependently enhanced functional connectivity during the decision-making task in PCC-centered circuits critical to reward- and risk-related decision-making. These data suggest that MDMA influences high-risk behavior and individual differences in reward and punishment learning. 2. Contribution of striatal circuits to impulsivity and relapse: Dysregulated striatal functioning, coupled with executive control deficits arising from abnormal frontal cortical function are considered key mechanisms in the development and maintenance of cocaine addiction. The same features are thought to underlie high trait impulsivity observed in cocaine-addicted populations. Employing rsFC, we sought to identify cortico-striatal circuit alterations in cocaine addiction and examine the degree to which circuit connectivity contributes to relapse risk and impulsivity among cocaine-addicted individuals. Relative to a group of healthy controls, residential treatment individuals for cocaine-addiction evidence reduced positive connectivity between the bilateral putamen and posterior insula and right postcentral gyrus. This reduction was most pronounced among individuals who went on to relapse within the first 30 days post-treatment. Scores on the BIS were higher in cocaine-addicted participants, an effect that was partially mediated by reduced putamen-posterior insula connectivity in this group. Cocaine addiction, relapse risk and impulsivity were associated with reduced connectivity in putamen-posterior insula/postcentral gyrus circuits implicated in temporal discounting and habitual responding. These findings provide new insight into the neurobiological mechanisms underlying impulsivity and relapse in cocaine addiction. 3. Cortico-amygdala circuits and relapse to cocaine use: The amygdala has been implicated in multiple relapse-related processes including craving, anxiety and reactivity to stress following both acute and protracted withdrawal from cocaine and other drugs of abuse. We examined resting connectivity within amygdala circuits among cocaine addicts during the final week of a 2-4 week treatment. To approximate relapse-related amygdala-circuitry identified within preclinical models we divided the amygdala into basolateral (BLA) and corticomedial (CMA) divisions. Relapse during the first 30 days post-treatment was associated with reduced resting connectivity between the left CMA and ventromedial prefrontal cortex/rostral anterior cingulate cortex (vmPFC/rACC). Individuals who didnt relapse during the first 30 days also showed suppressed connectivity between the bilateral BLA and visual processing regions (lingual gyrus/cuneus). These findings suggest that probing functional connectivity within neural circuits implicated in preclinical models of relapse to cocaine-seeking may provide a promising tool for assessing relapse risk in human cocaine-addicted individuals. 4. Prefrontal White matter impairment in substance users depends upon the catechol-o-methyl transferase (COMT) val158met polymorphism: individuals addicted to most chemical substances present with hypoactive dopaminergic systems as well as altered prefrontal white matter structure. Prefrontal dopamiinergic tone is under genetic control and is influenced by and modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal dopamine release. The COMT gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal dopaminergic tone. To determine if the COMT val158metgenotype influences white matter integrity (i.e., fractional anisotropy (FA)) in substance users, 126 healthy controls and 146 substance users underwent genotyping and MRI. A general linear model with two between-subjects factors (COMT genotype and addiction status) was performed using whole brain DTI to assess FA. A significant Genotype Drug Use status interaction was found in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were also drug users. These data suggest that Met/Met homozygous individuals, in the context of addiction, have increased susceptibility to white matter structural alterations, which might contribute to previously identified structural and functional PFC deficits in addiction.